Associations Between Lipoprotein Subfractions and Area and Density of Abdominal Muscle and Intermuscular Adipose Tissue: The Multi-Ethnic Study of Atherosclerosis

Abstract

Skeletal muscle quantity and quality decrease with older age, which is partly attributed to ectopic fat infiltration and has negative metabolic consequences. To inform efforts to preserve skeletal muscle with aging, a better understanding of biologic correlates of quantity and quality of muscle and intermuscular adipose tissue (IMAT) is needed. We used targeted lipidomics of lipoprotein subfractions among 947 Multi-Ethnic Study of Atherosclerosis participants to provide a detailed metabolic characterization of area and density of abdominal muscle and IMAT. Serum lipoprotein subfractions were measured at the first visit using 1H-Nuclear Magnetic Resonance spectroscopy. Muscle and IMAT area (cm2) and density (Hounsfield units) were estimated at visit 2 or 3 using computed tomography of the total abdominal, locomotion (psoas), and stabilization (paraspinal, oblique, rectus abdominis) muscles. We identified lipoprotein subfractions associated with body composition using linear regression adjusting for demographics, lifestyle, and multiple comparisons. Among 105 lipoprotein subfractions, 24 were associated with total muscle area (absolute standardized regression coefficient range: 0.07–0.10, p-values ≤ 0.002), whereas none were associated with total muscle density. When examining muscle subgroups, 25 lipoprotein subfractions were associated with stabilization muscle area, with associations strongest among the obliques. For total IMAT area, there were 27 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.09–0.13, p-values ≤ 0.002). Specifically, 27 lipoprotein subfractions were associated with stabilization IMAT area, with associations strongest among the oblique and rectus abdominis muscles. For total IMAT density, there were 39 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.10–0.19, p-values ≤ 0.003). Specifically, 28 and 33 lipoprotein subfractions were associated with IMAT density of locomotion and stabilization (statistically driven by obliques) muscles, respectively. Higher VLDL (cholesterol, unesterified cholesterol, phospholipids, triglycerides, and apolipoprotein B) and lower HDL (cholesterol and unesterified cholesterol) were associated with higher muscle area, higher IMAT area, and lower IMAT density. Several associations between lipoprotein subfractions and abdominal muscle area and IMAT area and density were strongest among the stabilization muscles, particularly the obliques, illustrating the importance of examining muscle groups separately. Future work is needed to determine whether the observed associations indicate a lipoprotein profile contributing to worse skeletal muscle with fat infiltration.

Evidence That Skeletal Muscles Modulate HDL-Cholesterol in Metabolic Healthy Young Adults

“…As a matter of fact, metabolic muscle dysfunction may occur in obesity. In fact, fatty infiltration with IMAT deposition and intracellular accumulation of lipids inside myocytes is commonly observed in obesity [ 30 , 31 ]. These alterations reduce muscle oxidative capacity while at the same time increasing anaerobic and glycolytic capacities and are responsible for metabolic dysfunction since they cause microinflammation, insulin resistance, and a decrease in the expression/activity of muscle LPL [ 32 , 33 , 34 , 35 , 36 ].…”

“…Moreover, LPL activity in skeletal muscle negatively correlates with plasma insulin levels and could be lowered by insulin resistance [ 37 ]. A recent lipidomic study showed that higher VLDL and lower HDL concentrations were associated with higher muscle area, higher IMAT area, and lower IMAT density (an index of muscle fatty infiltration) [ 31 ]. Therefore, low HDL-cholesterol in patients living with obesity and with higher fat mass could simply be one of the consequences of the decrease in the insulin sensitivity of skeletal muscles caused by muscle fat infiltration.…”

“…The relationship between HDL-cholesterol and SM could be bidirectional with muscle metabolic dysfunction contributing to decrease HDL-cholesterol and low HDL-cholesterol playing a role in causing muscle metabolic dysfunction. In fact, Marron et al (2021) [31] showed that IMAT accumulation could be facilitated by an inefficient reverse cholesterol transport. Moreover, it has been demonstrated that, in mice, HDL-cholesterol is required to preserve mitochondrial function and oxidative metabolism in SM [48].…”

Replacing sedentary time with light activity was associated with less adiposity across several depots in African ancestry men

“…Because adipose tissue depots were the outcome and physical activity was the main exposure of interest in our models, we did not adjust for BMI or waist circumference in our main models. Both BMI and waist circumference are common descendants of the adipose tissue depot outcomes [29] in this report, where adjusting for a common descendent can bias results [30]. We instead adjusted for height in our main models, that is, a measure of body size that is not a common descendent of the adipose tissue depot outcomes.…”

“…Physical activity is likely a common cause of the additional adipose tissue depots (e.g., visceral adiposity) and the adipose tissue depot outcome in the model. Specifically, the additional adipose tissue depots (e.g., visceral adiposity) are either [29]: (1) a common descendant of physical activity and not directly impacting the adipose tissue depot outcome examined in the model or (2) a mediator of the relationship between physical activity and the adipose tissue depot outcome in the model, where the incorrect inclusion of a mediator in the model will lead to an overadjustment bias [30].…”